Opiate abuse/dependence has profound social and economic effects in all parts of the world. Intravenous injection is the major route of illicit opiate drug administration in most countries, although abuse of oral prescription drugs has been recently increasing. While methadone clinics and other treatment programs can be effective, the expense of the support programs and medications can inhibit broad application of these methods to the target population, especially in less developed nations, and can be quite controversial in others. Without more effective treatment or prevention approaches for drug abuse, addiction to narcotics is very likely to accelerate further. An especially attractive alternative approach against opiate addiction in this context is immunization, a potentially powerful tool in assisting individuals to stop their abuse of these substances. Although there are many forms of opiate abuse, it is essential to focus experimental efforts for vaccine development on a limited number of specific agents to establish the effectiveness of this approach. Any effective vaccine for heroin will have to elicit high levels of antibodies that bind heroin, morphine, and other active metabolites, since concentrations of pharmacologically active opiates exceed the usual amounts of specific antibody. As our preliminary data shows, the outer membrane protein complex (OMPC) of Neisseria meningitidis is particularly attractive as a carrier for the morphine conjugate vaccine, since it elicits early, high level responses to the drug. The antibody response and the inhibition of morphine pharmacological effects can be directly evaluated in rodent model systems, permitting the rapid development of candidate vaccines. This proposal focuses on therapeutic heroin/morphine vaccines with these hypotheses: 1) Screening morphine linked to different carrier proteins or to a lipopeptide construct will allow selection of a vaccine that, along with appropriate adjuvant(s), can rapidly elicit a sufficient quantity and quality of specific antibody to block the pharmacological activity of heroin and its active metabolites. 2) The quality and quantity of the antibodies induced by these vaccines that can block opiate associated analgesia will also block heroin induced locomotor activity and reinstatement of heroin self administration in the rat model. Morphine will be conjugated to two highly effective protein carriers: OMPC and cholera toxin b (CTB). These conjugate vaccines will be compared with a novel self-adjuvanting lipopeptide vaccine prepared by D. C. Jackson (University of Melbourne, Australia). A panel of adjuvants compatible with human use will be examined to maximize the antibody quantity, quality (affinity), and persistence as well as the inhibition of opiate induced analgesia, locomotor activity, and reinstatement of drug self-administration. Successful completion of this project will continue the collaboration between American and Australian investigators that will be ideally positioned to get a vaccine quickly into clinical development studies. PUBLIC HEALTH RELEVANCE: Opiate abuse/dependence has had profound social and economic effects in all parts of the world. Intravenous injection is the dominant route of illicit opiate drug use, magnifying the health consequences of addiction through the spread of various blood borne pathogens. An especially attractive alternative approach to help treat opiate addiction is vaccination against these drugs, which could become a powerful tool in assisting individuals to stop their abuse of these substances. This research will develop such vaccines by attaching morphine to carrier molecules and testing immunization conditions that will stimulate high levels of antibody to block the effects of heroin and morphine on relapse to drug self administration in the mouse model of opiate abuse.